Vitamin D is known to be important in the regulation of calcium metabolism in animals and man. See, Harrison's Principals of Internal Medicine: Part Eleven, "Disorders of Bone and Mineral Metabolism," Chapter 335, E. Braunwald et al., (eds.), McGraw-Hill, New York (1987) pp. 1860-1865.
Vitamin D.sub.3 is synthesized endogenously in the skin of animals and man from 7-dehydrocholesterol by an ultraviolet-mediated photochemical reaction which breaks the B ring of the 7-dehydrocholesterol between carbon-4 and carbon-9 to form previtamin D.sub.3. The triene previtamin D.sub.3 is unstable and over time thermally converts to vitamin D.sub.3. At normal body temperature an equilibrium exists between previtamin D.sub.3 and vitamin D.sub.3, as seen below. As vitamin D.sub.3 is further metabolized in vivo this equilibrium shifts to the vitamin D.sub.3 form. ##STR1##
It is known that vitamin D.sub.3 must be hydroxylated in the carbon-1 and the carbon-25 position before it is activated, i.e., before it will produce a biological response. A similar metabolism appears to be required to activate the other forms of vitamin D, e.g., vitamin D.sub.2 and vitamin D.sub.4. As is generally understood and used herein, the term "vitamin D" is intended to include vitamins D.sub.3, D.sub.2, and D.sub.4. The term "activated vitamin D," as used herein, is intended to refer to vitamin D which has been hydroxylated in at least the carbon-1 position of the A ring, e.g., 1.alpha.-hydroxyvitamin D.sub.3.
Functionally, vitamin D is more appropriately considered a hormone than a vitamin. When activated, vitamin D interacts with a vitamin D receptor protein and this interaction ultimately results in some form of biological response. For example, 1.alpha.,25-dihydroxyvitamin D.sub.3 is known to be a potent stimulator of calcium absorption from the intestine, such absorption is mediated by the interaction of the 1.alpha.,25-dihydroxyvitamin D.sub.3 molecule and the vitamin D receptor protein located in the epithelial cells (enterocytes) which line the intestine.
In recent years it has become evident that the vitamin D receptor protein is widely distributed in the bodies of animals and man. Thus, it is not surprising that in addition to influencing calcium homeostasis, activated vitamin D has been implicated in osteogenesis, modulation of immune response, modulation of the process of insulin secretion by the pancreatic B cell, muscle cell function and the differentiation and growth of epidermal and hemopoietic tissues.
Such a wide range of biological actions suggests that the activated forms of vitamin D compounds should be valuable therapeutic agents for a wide range of maladies such as metabolic bone disease, osteoporosis, psoriasis, psoriatic arthritis, breast cancer and HIV infection. Unfortunately, when these agents are administered orally, the potent stimulation of calcium absorption by activated vitamin D can readily cause a dangerous hypercalcemia before the desired therapeutic response is obtained. For this reason, the activated vitamin D compounds are generally considered to have a low therapeutic to toxic ratio or low therapeutic index. Additionally, the presently known oral formulations when administered produce an unphysiologically rapid increase in the blood level of both calcium and activated vitamin D hormone followed by an almost as rapid decrease in the blood level of activated vitamin D hormone. Such rapid peaks and valleys of either the blood calcium or the activated vitamin D hormone are undesirable and perhaps harmful.
Recognizing the great potential of activated vitamin D as a therapeutic agent, alternative routes of administration which would allow higher sustained blood levels to be achieved and yet avoid the toxicity problems presented by the oral dosage form have been sought. To this end, an injectable form of 1.alpha.,25-dihydroxyvitamin D.sub.3 has been developed by Abbott Laboratories and is marketed under the trade name Calcijex for the management of hypocalcemia in patients undergoing chronic renal dialysis. Topical and transdermal forms of the drug have also been suggested by Holick, U.S. Pat. No. 4,230,701.
These alternative routes of administration, however, lack the convenience and the reliability of an oral dosage form and, to that extent, have diminished the practicality and attractiveness of activated vitamin D compounds as therapeutic agents. What is needed, is an oral dosage form which produces a more physiological sustained increase in the blood level of activated vitamin D and has a more acceptable therapeutic index than is presently possible with heretofore known oral formulations of activated vitamin D.